Abstract 746: T Cells Play an Important Role in the Pathogenesis of Angiotensin II Induced Hypertension.
Hypertension has been attributed to NADPH oxidase activation in the vessel, brain and kidney. How these systems interact to cause hypertension remains unclear. A circulating cell might mediate hypertension, perhaps by interacting with these organs. Lymphocytes possess an NADPH oxidase and angiotensin II causes their proliferation. Accordingly, we investigated the role of lymphocytes in angiotensin II dependent hypertension. The hypertension caused by angiotensin II (Ang II; 500 ng/kg/min) was markedly reduced in RAG-1−/− mice, which lack both T and B lymphocytes, compared to wild-type animals as measured by telemetry (MAP:124±4 vs. 142±4; n=12; p<0.01). The increase in aortic O2·− caused by Ang II was also blunted in RAG-1−/− mice (25±5 vs 217±30%; p<0.01). Adoptive transfer of T cells, but not B cells restored the hypertensive response to Ang II (MAP 157±5 mmHg; n=5), as well as the increase in vascular O2·− (210±50%). Adoptive transfer of T cells from p47phox−/− mice only partially restored the hypertensive response to Ang II (MAP: 139±4 vs. 157±5 mmHg; p<0.01). CD4−/− mice also displayed an intermediate response to Ang II. Ang II infusion caused a significant aortic T cell infiltration. Ang II infusion caused CD4+ cell activation as shown by increased CD69+ (6.0±1.3% vs 9.9±1.5% of CD4+; p<0.01; n=10) and CD25+ (7.6±0.5% vs 11.1±1.5% of CD4+; p<0.01) cells in the peripheral blood and spleen. CD44 and CCR5 were significantly increased in peripheral blood T cells. Ang II-induced hypertension was also associated with an increase in Th1 type cytokine production by peripheral and splenic T cells (IFN-gamma: 250±50%, TNF-alpha 185±20% and IL-2: 165±15%; p<0.05 n=6). These changes were accompanied by increased release of O2·− from T cells in Ang II treated animals (11.7 ± 3 vs 30.1 ± 8 pmol/mln). These data indicate that T cells play important role in Ang II mediated hypertension. We hypothesize that angiotensin II activates T cells, which infiltrate the kidney and vessels and release cytokines which in turn stimulate oxidant production in these tissues, leading to vasoconstriction, sodium retention and hypertension. T cell activation likely contributes to the inflammation associated with hypertension and provides a link between atherosclerosis and hypertension.